Endocrine Unit, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
Biochem Biophys Res Commun. 2011 Jun 3;409(2):235-40. doi: 10.1016/j.bbrc.2011.04.134. Epub 2011 May 5.
The ubiquitously expressed Calpains 1 and 2 belong to a family of calcium-dependent intracellular cysteine proteases. Both calpains are heterodimers consisting of a large subunit and a small regulatory subunit encoded by the gene Capns1. To investigate a role for the calpain small subunit in cells of the osteoblast lineage in vivo, we previously generated osteoblast-specific Capns1 knockout mice and characterized their bone phenotype. In this study, we further examined effects of low calcium and high fat diets on their bone, fat, and glucose homeostasis. Osteoblast-specific Capns1 knockout mice showed significantly reduced serum levels of total and uncarboxylated osteocalcin, and this was presumably due to their impaired bone formation and bone resorption. The reduced bone resorptive function of the mutant mice was also significant under a low calcium diet. Thus, these results suggest that reduced uncarboxylated osteocalcin levels of mutant mice were, at least in part, due to their osteoporotic bone with impaired bone resorptive function. Interestingly, unlike osteocalcin knockout mice, mutant mice on a normal chow diet were leaner than control littermates; this was likely due to their reduced food intake and overall lower energy homeostasis. To test this hypothesis, we next provided mutant mice with a high fat diet and further examined an effect of their reduced uncarboxylated osteocalcin levels on body composition and glucose metabolism. The average mean body weight of mutant mice became indistinguishable with that of controls after 2 weeks on a high fat diet, and continued to show an upward trend, at least, up to 6weeks. Moreover, mutant mice on a high fat diet exhibited a significant increase in serum levels of leptin and resistin, adipocyte-specific adipokines, and developed impaired glucose tolerance. Collectively, mice with osteoporosis and reduced bone resorptive function showed reduced serum uncarboxylated osteocalcin levels and were susceptible to increase body adiposity and develop impaired glucose tolerance under a high fat diet.
Calpain 1 和 2 广泛表达，属于钙依赖性细胞内半胱氨酸蛋白酶家族。两种钙蛋白酶都是由基因 Capns1 编码的大亚基和小调节亚基组成的异二聚体。为了研究钙蛋白酶小亚基在成骨细胞谱系细胞中的体内作用，我们之前生成了成骨细胞特异性 Capns1 敲除小鼠，并对其骨骼表型进行了表征。在这项研究中，我们进一步研究了低钙和高脂肪饮食对其骨骼、脂肪和葡萄糖稳态的影响。成骨细胞特异性 Capns1 敲除小鼠的血清总和未羧化骨钙素水平显著降低，这可能是由于其骨形成和骨吸收受损。在低钙饮食下，突变小鼠的骨吸收功能也明显降低。因此，这些结果表明，突变小鼠未羧化骨钙素水平降低至少部分是由于其骨质疏松性骨骼骨吸收功能受损所致。有趣的是，与骨钙素敲除小鼠不同，正常饮食的突变小鼠比对照同窝仔鼠更瘦；这可能是由于它们的食物摄入量减少和整体较低的能量稳态。为了验证这一假说，我们接下来给突变小鼠提供高脂肪饮食，并进一步研究其未羧化骨钙素水平降低对身体成分和葡萄糖代谢的影响。在高脂肪饮食 2 周后，突变小鼠的平均体重与对照组变得难以区分，并且至少在 6 周内持续呈上升趋势。此外，高脂肪饮食的突变小鼠血清瘦素和抵抗素水平显著升高，瘦素和抵抗素是脂肪细胞特异性脂肪因子，并出现葡萄糖耐量受损。总之，骨质疏松症和骨吸收功能降低的小鼠血清未羧化骨钙素水平降低，在高脂肪饮食下易发生体脂增加和葡萄糖耐量受损。
